Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA.

Specification and maturation of insulin(+) cells accompanies a transition in expression of Maf family of transcription factors. In development, MafA is expressed after specification of insulin(+) cells that are expressing another Maf factor, MafB; after birth, these insulin(+) MafA(+) cells stop MafB expression and gain glucose responsiveness. Current differentiation protocols for deriving insulin-producing ß-cells from stem cells result in ß-cells lacking both MafA expression and glucose-stimulated insulin secretion. So driving expression of MafA, a ß-cell maturation factor in endocrine precursors could potentially generate glucose-responsive MafA(+) ß cells. Using inducible transgenic mice, we characterized the final stages of ß-cell differentiation and maturation with MafA pause/release experiments. We found that forcing MafA transgene expression, out of its normal developmental context, in Ngn3(+) endocrine progenitors blocked endocrine differentiation and prevented the formation of hormone(+) cells. However, this arrest was reversible such that with stopping the transgene expression, the cells resumed their differentiation to hormone(+) cells, including α-cells, indicating that the block likely occurred after progenitors had committed to a specific hormonal fate. Interestingly, this delayed resumption of endocrine differentiation resulted in a greater proportion of immature insulin(+)MafB(+) cells at P5, demonstrating that during maturation the inhibition of MafB in ß-cell transitioning from insulin(+)MafB(+) to insulin(+)MafB(-) stage is regulated by cell-autonomous mechanisms. These results demonstrate the importance of proper context of initiating MafA expression on the endocrine differentiation and suggest that generating mature Insulin(+)MafA(+) ß-cells will require the induction of MafA in a narrow temporal window to achieve normal endocrine differentiation.

ß-cell preservation and regeneration for diabetes treatment: where are we now?

Over the last decade, our knowledge of ß-cell biology has expanded with the use of new scientific techniques and strategies. Growth factors, hormones and small molecules have been shown to enhance ß-cell proliferation and function. Stem cell technology and research into the developmental biology of the pancreas have yielded new methods for in vivo and in vitro regeneration of ß cells from stem cells and endogenous progenitors as well as transdifferentiation of non-ß cells. Novel pharmacological approaches have been developed to preserve and enhance ß-cell function. Strategies to increase expression of insulin gene transcription factors in dysfunctional and immature ß cells have ameliorated these impairments. Hence, we suggest that strategies to minimize ß-cell loss and to increase their function and regeneration will ultimately lead to therapy for both Type 1 and 2 diabetes.